The present invention relates to catalytic methods and compositions for use in highly regioselective and enantioselective alkylations of allylic substrates. Molybdenum, tungsten and chromium complexes of chiral ligands having such catalytic activity, particularly the molybdenum complexes, are described, along with methods for their use.
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Interest in molybdenum- and tungsten-catalyzed reactions of allyl substrates with nucleophiles has been promoted by the regioselectivity shown by these complexes, as compared to that of palladium complexes. See, for example, for molybdenum, Trost and Merlic, 1990, Rubio and Liebeskind, 1993, Trost and Hachiya, 1998; and for tungsten, Trost and Hung, 1983, and Trost et al., 1987. Palladium catalyzed reactions generally provide products from attack at the less substituted terminus. This regiochemistry (shown at eq 1, path a in FIG. 1) is particularly favored for alkylation of aryl-substituted allyl systems, even with catalysts having chiral ligands (Godleski, 1991). Molybdenum and tungsten catalysts, on the other hand, generally favor attack at the more substituted terminus (eq 1, path b). Complexes of these ms are also less costly than palladium catalysts.
Products of the type shown in reaction path (b), having high optical purity, find great value as building blocks in the synthesis of biologically useful compounds. A low-cost, versatile, stereoselective catalytic route to such compounds would thus be desirable.
In one aspect, the invention provides a catalytic organometallic composition, effective to catalyze the enantioselective alkylation of an allyl group bearing a leaving group at an allylic position. The composition comprises a metal atom selected from the group consisting of molybdenum, tungsten, and chromium, which is preferably molybdenum or tungsten and most preferably molybdenum, and coordinated thereto, a chiral ligand L1. The chiral ligand comprises a chiral component derived from a chiral diamine, and having first and second carbon atoms each bearing a binding group xe2x80x94NHxe2x80x94(Cxe2x95x90O)xe2x80x94B, wherein:
the above-referenced carbon atoms are connected by a direct bond or by a chain of one to three atoms comprising linkages selected from alkyl, alkyl ether, alkyl amino, and combinations thereof;
each group B is independently selected from alkyl, cycloalkyl, heterocycle, aryl, and aralkyl, as defined herein;
at least one group B is a N-heterocyclic or N-heteroaryl group CyN having an sp2 hybridized ring nitrogen atom effective to coordinate to said metal atom, and
at least one of the above-referenced carbon atoms is a chiral carbon atom bearing a further substituent effective to create a conformationally biased system containing the carbon atoms and the binding groups.
In preferred embodiments, the substituent (or substituents) on the above-referenced carbon atom(s) are independently selected from aryl, aralkyl, carbocycle, heterocycle, and secondary or tertiary alkyl having 3 or more, preferably 4 or more, carbon atoms. In one such embodiment, the substituents are aryl groups. In another embodiment, where both of the above-referenced carbon atoms are chiral and are adjacent, the substituents on these carbon atoms may together form a ring. This ring is typically a 5- to 7-membered carbocyclic ring, or a 5- to 7-membered heterocyclic ring having 1-3, preferably 1-2, ring atoms selected from oxygen, nitrogen and sulfur, and the remaining ring atoms carbon. It may be fused to one or more additional rings, preferably no more than two, and more preferably one or none. The ring or other substituents, particularly the cyclic substituents, may themselves be substituted with one or more groups selected from alkyl, alkenyl, aryl, aralkyl, alkoxy, aryloxy, acyl, acyloxy, carboxylic ester, amide, tertiary amine, nitro, and halogen.
In further embodiments, each said group B is a group CyN as defined above, and/or each said carbon atom is a chiral carbon atom bearing a substituent effective to create a conformationally biased system containing said carbon atoms and said binding groups. The carbon atoms are preferably connected by a direct bond.
Examples of the groups B described above as CyN, which may be the same or different on a given ligand, include, but are not limited to, pyridyl, quinolinyl, isoquinolyl, pyrimidyl, triazinyl, tetrazinyl, pyrazinyl, pyrazolyl, triazolyl, tetrazolyl, oxazinyl, oxazolyl, thiazolyl, imidazolyl, benzoxazole, benzimidazole, and dihydro derivatives of the above. N-heteroaryl groups are generally preferred. In one embodiment, at least one group B is a group CyN having an sp2 hybridized ring nitrogen which is xcex1 to a ring carbon atom which is linked to the carbonyl (Cxe2x95x90O) carbon of the binding group (referred to herein as an xe2x80x9cxcex1-linkedxe2x80x9d CyN). Examples of these groups include 2-pyridyl, 2-quinolinyl, 1- or 3-isoquinolyl, 2- or 4-pyrimidyl, 2-triazinyl, 4-tetrazinyl, 2-pyrazinyl, 3- or 5-pyrazolyl, 3- or 5-triazolyl, 2-tetrazolyl, 2-oxazinyl, 2- or 5-oxazolyl, 2- or 5-thiazolyl, 2- or 4-imidazolyl, 2-benzoxazole, 2-benzimidazole, and dihydro derivatives of the above.
The above-referenced carbon atoms of the chiral component are connected by a direct bond or by a chain of one to three atoms comprising linkages selected from alkyl, alkyl ether, alkyl amino, and combinations thereof. Preferably, they are connected by a direct bond, such that the chiral scaffold is derived from a 1,2-diamine. Examples of chiral 1,2-diamines that may be used as chiral scaffolds include 1R,2R-trans-diaminocyclohexane, 1R,2R-trans-diphenyl-1,2-ethanediamine, 3R,4R-trans-3,4-diamino-N-benzylpyrrolidine, 1R,2R-trans-diaminocycloheptane, 5R,6R-trans-5,6-diaminoindan, 1S-phenyl-1,2-ethanediamine, and the mirror image counterpart of any of the above. Examples of chiral ligands of the invention include those represented herein as ligands I-XV and their mirror image counterparts.
The catalytic organometallic composition of the invention is the product of a process which comprises contacting, in a suitable solvent, a chiral ligand L1, as defined above, with a complex (also referred to herein as the starting complex or precomplex) of a metal selected from tungsten (0), chromium (0), and molybdenum(0), ligands which form a stable complex with the m and are displaceable by ligand L1 under the conditions of said contacting. Such ligands include CO, cycloheptatriene, lower alkyl nitrile, and lower alkyl isonitrile. Preferred precomplexes for the preparation of the molybdenum catalysts include Mo(h3xe2x88x92C7H8)(CO)3 (cycloheptatriene molybdenum tricarbonyl), Mo(CO)3(CH3CH2CN)3, and Mo(CO)6. Tungsten and molybdenum complexes are preferred, with molybdenum being particularly preferred. Upon such contacting, the complex undergoes a ligand exchange reaction, such that L1 becomes coordinated to the m atom. The resulting composition is effective to catalyze the enantioselective alkylation of an allyl group bearing a leaving group at its allylic position.
In the above process, the molar ratio of the ligand L1 added to the hexacoordinate precomplex is generally between about 2:1 and about 1:1, and preferably between about 1.1:1 and about 1.5:1.
In another aspect, the invention provides a method of selectively alkylating an allyl group bearing a leaving group at the allylic position, under conditions effective to produce an alkylated product which is enriched in one of the possible isomeric products of such alkylation. The alkylation method comprises reacting the allyl group with an alkylating agent, in the presence of a catalytic amount of an alkylating catalyst. The alkylating catalyst is an organometallic complex having a metal atom selected from the group consisting of molybdenum, tungsten, and chromium, and coordinated thereto, a chiral ligand L1, as defined above. The m atom is preferably molybdenum or tungsten, and more preferably molybdenum.
In a related aspect, the method comprises reacting such a substrate with an alkylating agent in the presence of a catalytic composition formed by contacting, in a suitable solvent, catalytic amounts of (i) a complex of a m selected from the group consisting of molybdenum (0), tungsten (0), and chromium (0), having ligands which form a stable complex with the m and are displaceable by ligand L1 under the conditions of said contacting, and (ii) a chiral ligand L1, as defined above. Such ligands include CO, cycloheptatriene, lower alkyl nitrile, and lower alkyl isonitrile. The mole percent of said catalyst with respect to said substrate is preferably between about 0.5% and about 15%, and more preferably between about 1% and about 10%.
The reaction is carried out under conditions effective to produce an alkylated product which is enriched in one of the possible isomeric products of such alkylation. In one aspect, the alkylation is enantioselective, and preferably produces an alkylated product having an enantiomeric excess greater than 75%, preferably greater than 85% and more preferably greater than 95%. In another aspect, when the allyl group is nonsymmetrically substituted at its termini, the alkylation is regioselective, such that said allyl group is alkylated at its more sterically hindered terminus. Preferably, the regioselectivity of alkylation, defined as the ratio of product alkylated at the more sterically hindered terminus to product alkylated at the less sterically hindered terminus, is greater than 3:1, and more preferably greater than 9:1.
Preferred allyl substrates for the reaction are those in which the allyl group is substituted at one terminus with a substituent selected from aryl, heteroaryl, alkenyl, alkynyl, and alkyl. The reaction is especially useful for substrates in which neither allyl terminus is aryl substituted. This includes those in which one terminus is substituted with an alkyl group or with a non-aromatic conjugated polyene or enyne. In another embodiment of the method, where the allyl group has identical non-hydrogen substituents at its termini (with the exception of the leaving group), the alkylation is enantioselective with respect to the new chiral center formed at the alkylated terminus of said allyl group.
The alkylating agent is a preferably a stabilized carbanion, such as a carbanion of the form EExe2x80x2RCxe2x88x92M+, where M+ is a positively charged counterion, and each of E and Exe2x80x2 is a substituent which stabilizes the carbanion, e.g. an electron-withdrawing substituent selected from keto, carboxylic ester, cyano, and sulfonyl, or an aromatic or heteroaromatic group capable of stabilizing an xcex1-carbanion. Preferably, at least one of E and Exe2x80x2 is a carboxylic ester.
In a preferred embodiment of the method, the catalyst is formed in situ by ligand exchange of a soluble molybdenum(0) complex with ligand L1. The complex, as described above, comprises ligands which are effective to form a stable complex with Mo(0) and which are displaceable by ligand L1 under the conditions of the ligand exchange. Preferred ligands include cycloheptatriene, CO, lower alkyl nitrile, and lower-alkyl isonitrile.
These and other objects and features of the invention will become more fully apparent when the following detailed description of the invention is read in conjunction with the accompanying drawings.